Tetrahydrocannabutol (THCB) and Cannabidibutol

One of the essential parameters that can affect the biological activity of THC-like cannabinoids is the length of the C3 alkyl chain. A minimum of three carbons are necessary for receptor binding; activity then increases with increasing number of carbons up to a maximum of eight carbons; for n > 8, activity begins to decrease again (

Bow and Rimoldi, 2016

). Cannazza and colleagues have recently reported two new phytocannabinoids, tetrahydrocannabutol (THCB) and cannabidibutol, both with linear alkyl side chains containing four carbon atoms (

Citti et al., 2019a

; 

Linciano et al., 2020

). THCB has thrice the affinity of THC for CB1, with unchanged affinity for CB2 (

Bow and Rimoldi, 2016

). Docking simulations of THCB@ CB1 found binding poses similar to those exhibited by THC and THCV. The main difference between the three ligands was observed in the position of the aliphatic side chain: the butyl chain of THCB does not extend down the TM3-TM5-TM6 tunnel like the pentyl chain of THC (Figure 10C); instead, like the propyl chain of THCV it binds to the small hydrophobic subpocket located near the entrance of the tunnel (Figure 10D). This leads to THCB‘s optimal hydrophobic interaction with F170, F200, and L387, accounting for its exceptional affinity for the CB1 receptor (Figure 10E).

Tetrahydrocannabiphorol (THCP) and Cannabidiphorol (CBDP)

In late 2019, Cannazza and coworkers reported the isolation of two additional phytocannabinoids: tetrahydrocannabiphorol (THCP) and cannabidiphorol, both with C7 linear alkyl side chains (

Citti et al., 2019b

). THCP has exceptional affinity to both CB1 and CB2, with a Ki of 1.2 and 6.2 nM, respectively, 33-fold the affinity of THC for CB1 and 13-fold higher than THCB. THCP binds to the active conformation of CB1 in an L-shaped pose, approximating that of THC in the presence of CBD (

Chung et al., 2019

), with the tetrahydro-6H-benzo[c]chromene ring system occupying the hydrophobic orthosteric pocket. The resorcinyl moiety participates in two edge-to-face π-π interactions with F170 and F268, and the C1 hydroxyl group hydrogen bonds with S383 (Figure 10F). Interestingly, the heptyl chain at C3 extended into a long hydrophobic tunnel formed by L193, V196, Y275, I271, L276, W279, L359, F379, and M363, formed by TM3, TM5, and TM6, along its entire length, maximizing the hydrophobic interactions with the residues along the side of the channel (Figures 10F and 10G). In contrast, the tunnel is only partially occupied by the shorter pentyl chain of THC, helping to account for THCP‘s far higher affinity. This orientation is also different than the pose predicted for the shorter alkyl chain homologs, THCV and THCB, where the chain sits in the side hydrophobic pocket instead. In a murine model, THCP showed promising pharmacological activities associated with CB1 agonists including reduced motility, analgesia, catalepsy, and decreased rectal temperature.